Aldehyde dehydrogenases (ALDHs) are intracellular enzymes responsible for oxidizing aldehydes. Substrates for ALDHs include acetyldehyde, an intermediate in ethanol metabolism, and biogenic amines produced during catecholamine catabolism. (Russo et al., Cancer Res. 48: 2963-2968 (1988)). ALDH has also been reported to play a crucial role in the conversion of vitamin A to its active metabolite, retinoic acid. (Labrecque et al., Biochem. Cell Biol. 71:85-89 (1993); Yoshida et al., Enzyme 46:239-244 (1992)).
High enzymatic activity of aldehyde dehydrogenase (ALDH) has been shown to be a characteristic feature of primitive hematopoeitic progenitor cells in mice and humans. (Kohn et al., Biochem. Pharmacol. 34:3465-3471 (1985); Kastan et al., Blood 75:1947-1950 (1990)). ALDH activity has been previously used as a marker to assess for the quality of hematopoeitic stem cell transplants. (Lioznov et al., Bone Marrow Transplant. 35:909-914 (2005)).
A number of studies seem to suggest that ALDH confers resistance of cells to cyclophosphamide, which is routinely used for the treatment of autoimmune diseases and cancer. For example, cyclophosphamide is included in various chemotherapeutic regiments for treatment of cancer and high-dose cyclophosphamide (for example, 50 mg/kg/day×4 days) has been used for the treatment of certain autoimmune diseases such as, for example, severe aplastic anemia. High dose cyclophosphamide therapy appears to be effective than the low-dose therapy which usually requires daily oral dosing or monthly intravenous pulses at 500-1000 mg/m2 and has a higher risk of malignancies and premature menopause and/or infertility. High dose cyclophosphamide therapy, however, is not suitable for all patients, because of higher toxicity.
It also has been observed that in patients receiving high-dose cyclophosphamide therapy for autoimmune diseases, patients who achieved maximal immunosuppression following the therapy as indicated by their white blood cell count (WBC) reaching 0 experience a better clinical outcome and lessened risk of disease relapse than patients whose white blood cell count did not reach zero following therapy.
Analysis of the banked blood of a series of patients following high-dose cyclophosphamide treatment demonstrated that patients who reached a white blood cell count of 0 and subsequently enjoyed a better clinical outcome had much had a much lower level of ALDH activity than the patient who relapsed without reaching a WBC of 0.
The observed outcomes and the ALDH measures obtained from the banked blood samples suggest that treatment success depends on both the ability of hematopoietic stem cells to resist high-dose cyclophosphamide as a result of their elevated ALDH and on a sufficiently weak or absent ALDH level in peripheral lymphocytes which renders those cells sensitive to treatment.
It is generally difficult to predict which patients might be suitable for high-dose cyclophosphamide. It is also generally difficult to predict which patients might experience treatment failure or disease relapse following high-dose cyclophosphamide therapy due to their peripheral lymphocytes being resistant to the administered drug dose.